Chapter 53 Aminoglycoside Antibiotics

These are a group of natural and semisynthetic antibiotics having polybasic amino groups linked glycosidically to two or more aminosugar (streptidine, 2-deoxy streptamine, garosamine) residues.

Unlike penicillin, which was a chance discovery, aminoglycosides are products of deliberate search for drugs effective against gram-negative bacteria. Streptomycin was the first member discovered in 1944 by Waksman and his colleagues. It assumed great importance because it was active against tubercle bacilli. Others were produced later, and now aminoglycosides are a sizable family. All aminoglycosides are produced by soil actinomycetes and have many common properties (see box).

Systemic aminoglycosides

Streptomycin Amikacin

Gentamicin Sisomicin

Kanamycin Netilmicin

Tobramycin Paromomycin

Topical aminoglycosides

Neomycin Framycetin

Common properties of aminoglycoside antibiotics

1.All are used as sulfate salts, which are highly water soluble; solutions are stable for months.

2.They ionize in solution; are not absorbed orally; distribute only extracellularly; do not penetrate brain or CSF.

3.All are excreted unchanged in urine by glomerular filtration.

4.All are bactericidal and more active at alkaline pH.

5.They act by interfering with bacterial protein synthesis.

6.All are active primarily against aerobic gram-negative bacilli and do not inhibit anaerobes.

7.There is only partial cross resistance among them.

8.They have relatively narrow margin of safety.

9.All exhibit ototoxicity and nephrotoxicity.

MECHANISM OF ACTION

The aminoglycosides are bactericidal antibiotics, all having the same general pattern of action which may be described in two main steps:

(a)Transport of the aminoglycoside through the bacterial cell wall and cytoplasmic membrane.

(b)Binding to ribosomes resulting in inhibition of protein synthesis.

Transport of aminoglycoside into the bacterial cell is a multistep process. They diffuse across the outer coat of gram-negative bacteria through porin channels. Entry from the periplasmic space across the cytoplasmic membrane is carrier mediated which is linked to the electron transport chain. Thus, penetration is dependent upon maintenance of a polarized membrane and on oxygen dependent active processes (energy

dependent phase I or EDP1 entry). These processes are inactivated under anaerobic conditions; anaerobes are not sensitive and facultative

anaerobes are more resistant when O2 supply is deficient, e.g. inside big abscesses. Penetration is also favoured by high pH; aminoglycosides are ~20 times more active in alkaline than in

acidic medium. Inhibitors of bacterial cell wall (β-lactams, vancomycin) enhance entry of aminoglycosides and exhibit synergism.

Once inside the bacterial cell, streptomycin binds to 30S ribosomes, but other aminoglycosides bind to additional sites on 50S subunit, as well as to 30S-50S interface. They freeze initiation of protein synthesis (see Fig. 52.1), prevent polysome formation and promote their disaggregation to monosomes so that only one ribosome is attached to each strand of mRNA. Binding of aminoglycoside to 30S-50S juncture causes distortion of mRNA codon recognition resulting in misreading of the code: one or more

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wrong amino acids are entered in the peptide chain and/or peptides of abnormal lengths are produced. Different aminoglycosides cause misreading at different levels depending upon their selective affinity for specific ribosomal proteins.

The cidal action of these drugs appears to be based on secondary changes in the integrity of bacterial cell membrane, because other antibiotics which inhibit protein synthesis (tetracyclines, chloramphenicol, erythromycin) are only static. After exposure to aminoglycosides, sensitive bacteria become more permeable; ions, amino acids and even proteins leak out followed by cell death. This probably results from incorporation of the defective proteins into the cell membrane. One of the consequences of aminoglycoside induced alteration of cell membrane is augmentation of the carriermediated energy-dependent phase II (EDP2) entry of the antibiotic. This reinforces their lethal action.

The cidal action of aminoglycosides is concentration dependent, i.e. rate of bacterial cell killing is directly related to the ratio of the peak antibiotic concentration to the MIC value. They also exert a long and concentration dependent ‘postantibiotic effect’ (see p. 697). It has, therefore, been argued that despite their short t½ (2–4 hr), single injection of the total daily dose of aminoglycoside may be more effective and possibly less toxic than its conventional division into 2–3 doses.

MECHANISM OF RESISTANCE

Resistance to aminoglycosides is acquired by one of the following mechanisms:

(a) Acquisition of cell membrane bound inactivating enzymes which phosphorylate/ adenylate or acetylate the antibiotic. The conjugated aminoglycosides do not bind to the target ribosomes and are incapable of enhancing active transport like the unaltered drug. These enzymes are acquired mainly by conjugation and transfer of plasmids. Nosocomial microbes have become

rich in such plasmids, some of which encode for multidrug resistance. This is the most important mechanism of development of resistance to aminoglycosides. Susceptibility of different aminoglycosides to these enzymes differs. Thus, cross resistance was found between gentamicin and tobramycin or netilmicin, but not between these and streptomycin. Many nosocomial gram-negative bacilli resistant to gentamicin/tobramycin respond to amikacin.

(b)Mutation decreasing the affinity of ribosomal proteins that normally bind the aminoglycoside: this mechanism can confer high degree resistance, but operates to a limited extent, e.g. E. coli that develop streptomycin resistance by single step mutation do not bind the antibiotic on the polyribosome. Only a few other instances are known. This type of resistance is specific for a particular aminoglycoside.

(c)Decreased efficiency of the aminoglycoside transporting mechanism: either the pores in the outer coat become less permeable or the active transport is interfered. This again is not frequently encountered in the clinical setting. In some Pseudomonas which develop resistance, the antibiotic induced 2nd phase active transport has been found to be deficient.

SHARED TOXICITIES

The aminoglycosides produce toxic effects which are common to all members, but the relative propensity differs (see Table 53.1).

1. Ototoxicity This is the most important dose and duration of treatment related adverse effect. The vestibular or the cochlear part may be primarily affected by a particular aminoglycoside. These drugs are concentrated in the labyrinthine fluid and are slowly removed from it when the plasma concentration falls. Ototoxicity is greater when plasma concentration of the drug is persistently high and above a threshold value. For gentamicin this is estimated to be ~ 2 μg/ml; if the trough level is above this value, vestibular damage becomes concentration dependent. It is recommended that dosing of gentamicin should be such that the measured trough plasma concentration is < 1 μg/ml to avoid toxicity. The vestibular/cochlear sensory cells and hairs undergo concentration dependent destructive changes. Aminoglycoside ear drops can cause ototoxicity when instilled in patients with perforated eardrum; are contraindicated in them.

Cochlear damage It starts from the base and spreads to the apex; hearing loss affects the high frequency sound first, then progressively encompasses the lower frequencies. No regeneration of the sensory cells occurs; auditory nerve fibres degenerate in a retrograde manner—deafness is permanent. Older patients and those with preexisting hearing defect are more susceptible. Initially, the cochlear toxicity is asymptomatic and can be detected only by audiometry. Tinnitus then appears, followed by progressive hearing loss. On stopping the drug, tinnitus disappears in 4–10 days, but frequency loss persists.

Vestibular damage Headache is usually first to appear, followed by nausea, vomiting, dizziness, nystagmus, vertigo and ataxia. When the drug is stopped at this stage, it passes into a chronic phase lasting 6 to 10 weeks in which the patient is asymptomatic while in bed and has difficulty only during walking. Compensation by visual and proprioceptive positioning and recovery (often incomplete) occurs over 1–2 years. Permanency of changes depends on the extent of initial damage and the age of the patient (elderly have poor recovery).

2.Nephrotoxicity It manifests as tubular damage resulting in loss of urinary concentrating power, low g.f.r., nitrogen retention, albuminuria and casts. Aminoglycosides attain high concentration in the renal cortex (proximal tubules) and toxicity is related to the total amount of the drug received by the patient. However, in patients with normal renal function, single daily dosing regimen appears to cause lesser nephrotoxicity than the conventional thrice daily dosing. It is more in the elderly and in those with preexisting kidney disease. Provided the drug is promptly discontinued renal damage caused by aminoglycosides is totally reversible. It has been postulated that aminoglycosides interfere with the production of PGs in the kidney and that this is causally related to the reduced g.f.r. An important implication of aminoglycosideinduced nephrotoxicity is reduced clearance of the antibiotic resulting in higher and more persistent blood levels causing enhanced ototoxicity. Streptomycin and possibly tobramycin are less nephrotoxic than the other aminoglycosides.

3.Neuromuscular blockade All aminoglycosides

reduce ACh release from the motor nerve endings. They interfere with mobilization of centrally located synaptic vesicles to fuse with the terminal membrane (probably by antagonizing Ca2+) as well as decrease the sensitivity of the muscle endplates to ACh. The effect of this action is not manifested ordinarily in the clinical use of these drugs. However, apnoea and fatalities have occurred when streptomycin/neomycin was put into peritoneal or pleural cavity after an operation, especially if a curare-like muscle relaxant was administered during surgery. Rapid absorption form the peritoneum/pleura produces high blood levels and adds to the residual action of the neuromuscular blocker.

Neomycin and streptomycin have higher propensity than kanamycin, gentamicin or amikacin, while tobramycin is least likely to produce this effect. The neuromuscular block produced by aminoglycosides can be partially antagonized by i.v. injection of a calcium salt. Neostigmine has inconsistent reversing action.

Myasthenic weakness is accentuated by these drugs. Neuromuscular blockers should be used cautiously in patients

receiving aminoglycosides.

PRECAUTIONS AND INTERACTIONS

1.Avoid aminoglycosides during pregnancy: risk of foetal ototoxicity.

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2.Avoid concurrent use of other nephrotoxic drugs, e.g. NSAIDs, amphotericin B, vancomycin, cyclosporine and cisplatin.

3.Cautious use of other potentially ototoxic drugs like vancomycin, minocycline and furosemide, though clinical evidence of potentiated ototoxicity is meagre.

4.Cautious use in patients >60 years age and in those with kidney damage.

5.Cautious use of muscle relaxants in patients receiving an aminoglycoside.

6.Do not mix aminoglycoside with any drug in the same syringe/infusion bottle.

PHARMACOKINETICS

All systemically administered aminoglycosides have similar pharmacokinetic features. They are highly ionized, and are neither absorbed nor destroyed in the g.i.t. However, absorption from injection site in muscles is rapid: peak plasma levels are attained in 30–60 minutes. They are distributed only extracellularly, so that volume of distribution (~0.3 L/kg) is nearly equal to the extracellular fluid volume. Low concentrations are attained in serous fluids like synovial, pleural and peritoneal, but these levels may be significant after repeated dosing. Relatively higher concentrations are present in endolymph and renal cortex, which are responsible for ototoxicity and nephrotoxicity. Penetration in respiratory secretions is poor. Concentrations in CSF and aqueous humour are nontherapeutic even in the presence of inflammation. Aminoglycosides cross placenta and can be found in foetal blood/amniotic fluid. Their use during pregnancy can cause hearing loss in the offspring, and must be avoided unless absolutely essential. The plasma protein binding of aminoglycosides is clinically insignificant, though streptomycin is bound to some extent.

Aminoglycosides are not metabolized in the body, and are excreted unchanged in urine. Glomerular filtration is the main channel, because tubular secretion as well as reabsorption are negligible. The plasma t½ ranges between 2–4 hours, but small amount of drug persists

longer in tissues. After chronic dosing, the drug may be detectable in urine for 2–3 weeks. Renal clearance of aminoglycosides parallels creatinine clearance (CLcr), and is approximately 2/3 of it. The t½ is prolonged and accumulation occurs in patients with renal insufficiency, in the elderly and in neonates who have low g.f.r. Reduction in dose or increase in dose-interval is essential in these situations. This should be done according to the measured CLcr. Nomograms are available to help calculation of CLcr, but actual measurement in the individual patient is preferable. Generally, there is no need to reduce the daily dose till CLcr is above 70 ml/min. A simple guide to dose calculation below this level is given in the box.

Guideline for dose adjustment of gentamicin in renal insufficiency

DOSING REGIMENS

Because of low safety margin, the daily dose of systemically administered aminoglycosides must be precisely calculated accordingly to body weight and level of renal function. For an average adult with normal renal function (CLcr >70 ml/min), the usual doses are:

Gentamicin/tobramycin/

sisomicin/netilmicin

Streptomycin/

kanamycin/amikacin

Considering the short t½ (2–4 hr) of aminoglycosides the daily doses are conventionally divided into 3 equal parts and injected i.m. (or i.v. slowly over 60 min) every 8 hours. However, most authorities now recommend a single total daily dose regimen for patients with normal renal function. This is based on the considerations that:

•Aminoglycosides exert concentration dependent bactericidal action and a long postantibiotic effect, therefore higher plasma concentrations attained after the single daily dose will be equally or more effective than the divided doses.

•With the single daily dose, the plasma concentration will remain subthreshold for ototoxicity and nephrotoxicity for a longer period each day allowing washout of the drug from the endolymph and the renal cortex.

Several comparative studies with gentamicin and few other aminoglycosides and meta-analyses of these studies have validated this concept. The single daily dose regimen has been found to be less nephrotoxic, but no dosing regimen appears to be less ototoxic than another. Both regimens are equally effective. Single daily doses are also more convenient and cheaper (require less man power). However, the safety of the high dose extended interval regimen in patients with renal insufficiency and in children is not established, and is therefore avoided. It is also not recommended when gentamicin is combined with a β-lactam antibiotic for obtaining cidal effect in bacterial endocarditis, etc.

Gentamicin

It was the 3rd systemically administered aminoglycoside antibiotic to be introduced for clinical use, and was obtained from Micromonospora purpurea in 1964. It quickly surpassed streptomycin because of higher potency and broader spectrum of activity. Currently, it is the most commonly used aminoglycoside for acute infections and may be considered prototype of the class. It is active mainly against aerobic gramnegative bacilli, including E. coli, Klebsiella pneumoniae, Enterobacter, H. influenzae, Proteus, Serratia and Pseudomonas aeruginosa. Many strains of Brucella, Campylobacter, Citrobacter, Fransisella and Yersinia are also sensitive. Limited number of gram-positive bacteria are susceptible, especially Staph. aureus, Strep. faecalis and some Listeria, but

Strep. pyogenes, Strep. pneumoniae and enterococci are usually insensitive.

Gentamicin is ineffective against Mycobacterium tuberculosis and other mycobacteria. It is more potent (its MIC are lower) than streptomycin, kanamycin and amikacin, but equally potent as tobramycin, sisomicin and netilmicin. Bacteria that acquire resistance against gentamicin generally exhibit cross resistance to tobramycin and sisomicin also. It synergises with β-lactam antibiotics, especially against Enterococcus (endocarditis) and Pseudomonas (meningitis).

Dose: 3–5 mg/kg/day (single dose or divided in 3 doses) i.m. or in an i.v. line over 30–60 min. GARAMYCIN,GENTASPORIN,GENTICYN 20, 60,80, 240mg per vial inj; also 0.3% eye/ear drops, 0.1% skin cream.

Uses Gentamicin is the cheapest (other than streptomycin) and the first line aminoglycoside antibiotic. It is often added when a combination antibiotic regimen is used empirically to treat serious infections by extending the spectrum of coverage. Because of low therapeutic index, its use should be restricted to serious gram-negative bacillary infections.

1. Gentamicin is very valuable for preventing and treating respiratory infections in critically ill patients; in those with impaired host defence (receiving anticancer drugs or high-dose corticosteroids; AIDS; neutropenic), patients in resuscitation wards, with tracheostomy or on respirators; postoperative pneumonias; patients with implants and in intensive care units. It is often combined with a penicillin/cephalosporin or another antibiotic in these situations. However, resistant strains have emerged in many hospitals and nosocomial infections are less amenable to gentamicin now. Another aminoglycoside (tobramycin, amikacin, netilmicin) is then selected on the basis of the local sensitivity pattern, but strains resistant to gentamicin are generally cross resistant to tobramycin and sisomicin. Aminoglycosides should not be used to treat community acquired pneumonias which are mostly caused by gram-positive cocci and anaerobes.

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Gentamicin is often added to the peritoneal dialysate to prevent or treat peritonitis.

2.Pseudomonas, Proteus or Klebsiella infections: burns, urinary tract infection, pneumonia, lung abscesses, osteomyelitis, middle ear infection, septicaemia, etc., caused mostly by the above bacteria are an important area of use of gentamicin. It may be combined with piperacillin or a third generation cephalosporin for serious infections. Topical use on infected burns and in conjunctivitis is permissible.

3.Meningitis caused by gram negative bacilli: Because this is a serious condition, drug combinations including an aminoglycoside are often used. The third generation cephalosporins alone or with an aminoglycoside are favoured for this purpose.

4.Subacute bacterial endocarditis (SABE): Gentamicin (1 mg/kg 8 hourly i.m.) is generally combined with penicillin/ampicillin/vancomycin.

Streptomycin

It is the oldest aminoglycoside antibiotic obtained from Streptomyces griseus; which was used extensively in the past, but is now practically restricted to treatment of tuberculosis. It is less potent (MICs are higher) than many other aminoglycosides. The antimicrobial spectrum of streptomycin is relatively narrow: primarily covers aerobic gram-negative bacilli. Sensitive organisms are—H. ducreyi, Brucella, Yersinia pestis, Francisella tularensis, Nocardia, Calym. granulomatis, M. tuberculosis. Only few strains of E. coli, H. influenzae, V. cholerae, Shigella, Klebsiella, enterococci and some gram-positive cocci are now inhibited, that too at higher concentrations. All other organisms including Pseudomonas are unaffected.

Resistance Many organisms rapidly develop resistance to streptomycin, either by one-step mutation or by acquisition of plasmid which codes for inactivating enzymes. In the intestinal and urinary tracts, resistant organisms may emerge within 2 days of therapy. E. coli, H. influenzae, Str. pneumoniae, Str. pyogenes, Staph. aureus

have become largely resistant. If it is used alone, M. tuberculosis also become resistant.

Streptomycin dependence Certain mutants grown in the presence of streptomycin become dependent on it. Their growth is promoted rather than inhibited by the antibiotic. This occurs when the antibiotic induced misreading of the genetic code becomes a normal feature for the organism. This phenomenon is probably significant only in the use of streptomycin for tuberculosis.

Cross resistance Only partial and often unidirectional cross resistance occurs between streptomycin and other aminoglycosides.

Adverse effects About 1/5 patients given streptomycin 1 g BD i.m. experience vestibular disturbances. Auditory disturbances are less common.

Streptomycin has the lowest nephrotoxicity among aminoglycosides; probably because it is not concentrated in the renal cortex. Hypersensitivity reactions are rare; rashes, eosinophilia, fever and exfoliative dermatitis have been reported. Anaphylaxis is very rare. Topical use is contraindicated for fear of contact sensitization.

Superinfections are not significant. Pain at injection site is common. Paraesthesias and scotoma are occasional. It is contraindicated during pregnancy due to risk of foetal ototoxicity.

AMBISTRYN-S 0.75, 1 g dry powder per vial for inj.

Acute infections: 1 g (0.75 g in those above 50 yr age) i.m. OD or BD for 7–10 days.

Tuberculosis: 1 g or 0.75 g i.m. OD or thrice weekly for 30–60 days.

Uses

1.Tuberculosis: see Ch. 55.

2.Subacute bacterial endocarditis (SABE): Streptomycin

(now mostly gentamicin) is given in conjunction with penicillin/ ampicillin/vancomycin for 4–6 weeks.

3.Plague: It effects rapid cure (in 7–12 days); may be employed in confirmed cases, but tetracyclines have been more commonly used for mass treatment of suspected cases during an epidemic.

4.Tularemia: Streptomycin is the drug of choice for this rare disease; effects cure in 7–10 days. Tetracyclines are the alternative drugs, especially in milder cases.

In most other situations, e.g. urinary tract infection, peritonitis, septicaemias, etc. where

streptomycin was used earlier, gentamicin or one of the newer aminoglycosides is now preferred due to widespread resistance to streptomycin and its low potency.

Oral use of streptomycin for diarrhoea is banned in India.

Kanamycin

Obtained from S. kanamyceticus (in 1957), it was the second systemically used aminoglycoside to be developed after streptomycin. It is similar to streptomycin in all respects including efficacy against M. tuberculosis and lack of activity on Pseudomonas. However, it is more toxic, both to the cochlea and to kidney. Hearing loss, which is irreversible, is more common than vestibular disturbance.

Because of toxicity and narrow spectrum of activity, it has been largely replaced by other aminoglycosides for treatment of gram-negative bacillary infections; may be used only if mandated by sensitivity report of the infecting strain. It is occasionally used as a second line drug in resistant tuberculosis. Dose: 0.5 g i.m. BD (15 mg/kg/day); KANAMYCIN, KANCIN, KANAMAC 0.5 g, 0.75 g, 1.0 g inj.

Tobramycin

It was obtained from S. tenebrarius in the 1970s. The antibacterial and pharmacokinetic properties, as well as dosage are almost identical to gentamicin, but it is 2–4 times more active against Pseudomonas and Proteus, including some resistant to gentamicin, but majority are cross resistant. However, it is not useful for combining with penicillin in the treatment of enterococcal endocarditis. It should be used only as an alternative to gentamicin. Serious infections caused by Pseudomonas and Proteus are its major indications. Ototoxicity and nephrotoxicity is probably less than gentamicin.

Dose: 3–5 mg/kg day in 1–3 doses.

TOBACIN 20, 60, 80 mg in 2 ml inj. 0.3% eye drops. TOBRANEG 20, 40, 80 mg per 2 ml inj, TOBRABACT 0.3% eye drops.

Amikacin

It is a semisynthetic derivative of kanamycin to which it resembles in pharmacokinetics, dose and toxicity. The outstanding feature of amikacin is its resistance to bacterial aminoglycoside inactivating enzymes. Thus, it has the widest spectrum of activity, including many organisms resistant to other aminoglycosides. However, relatively higher doses are needed for Pseudomonas, Proteus and Staph. infections.

The range of conditions in which amikacin can be used is the same as for gentamicin. It is recommended as a reserve drug for empirical treatment of hospital acquired gram-negative bacillary infections where gentamicin/tobramycin resistance is high. It is effective in tuberculosis, but used only for multidrug resistant infection. More hearing loss than vestibular disturbance occurs in toxicity.

Dose: 15 mg/kg/day in 1–3 doses; urinary tract infection 7.5 mg/kg/day.

AMICIN, MIKACIN, MIKAJECT 100 mg, 250 mg, 500 mg in 2 mlinj.

Sisomicin

Introduced in 1980s, it is a natural aminoglycoside from Micromonospora inyoensis that is chemically and pharmacokinetically similar to gentamicin, but somewhat more potent on Pseudomonas, a few other gram-negative bacilli and β haemolytic Streptococci. It is moderately active on faecal Streptococci—can be combined with penicillin for SABE. However, it is susceptible to aminoglycoside inactivating enzymes and offers no advantage in terms of ototoxicity and nephrotoxicity. It can be used interchangeably with gentamicin for the same purposes in the same doses.

ENSAMYCIN, SISOPTIN 50 mg, 10 mg (pediatric) per ml in 1 ml amps, 0.3% eyedrops, 0.1% cream.

Netilmicin

This semisynthetic derivative of gentamicin has a broader spectrum of activity than gentamicin. It is relatively resistant to many aminoglycoside inactivating enzymes and thus effective against some gentamicin-resistant strains. It is more active against Klebsiella, Enterobacter and

Staphylococci, but less active against Ps. aeruginosa.

Pharmacokinetic characteristics and dosage of netilmicin are similar to gentamicin. Experimental studies have shown it to be less ototoxic than gentamicin and tobramycin, but clinical evidence is inconclusive: hearing loss occurs, though fewer cases of vestibular damage have been reported.

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A marginal improvement in antibacterial spectrum, clinical efficacy and possibly reduced toxicity indicates that netilmicin could be a useful alternative to gentamicin.

Dose: 4–6 mg/kg/day in 1–3 doses; NETROMYCIN 10, 25, 50 mg in 1 ml, 200 mg in 2 ml and 300 mg in 3 ml inj., NETICIN 200 mg (2 ml), 300 mg (3 ml) inj.

Neomycin

Obtained from S. fradiae, it is a wide-spectrum aminoglycoside, active against most gramnegative bacilli and some gram-positive cocci. However, Pseudomonas and Strep. pyogenes are not sensitive. Neomycin is highly toxic to the internal ear (mainly auditory) and to kidney. It is, therefore, not used systemically. Absorption from the g.i.t. is minimal. Oral and topical administration does not ordinarily cause systemic toxicity.

Dose: 0.25–1 g QID oral, 0.3–0.5% topical.

NEOMYCIN SULPHATE 350, 500 mg tab, 0.3% skin oint, 0.5% skin cream, eye oint.

NEBASULF: Neomycin sulph. 5 mg, bacitracin 250 U, sulfacetamide 60 mg/g oint. and powder for surface application. POLYBIOTIC CREAM: Neomycin sulph. 5 mg, polymyxin 5,000 IU, gramicidin 0.25 mg/g cream.

NEOSPORIN: Neomycin 3400 iu, polymyxin B 5000 iu, bacitracin 400 iu/g oint and powder for surface application. NEOSPORIN- H: Neomycin 3400 iu, polymyxin B 5000 iu, hydrocortisone 10 mg per g oint and per ml ear drops.

Uses

1.Topically (often in combination with polymyxin, bacitracin, etc.) for infected wound, ulcers, burn, external ear infections, conjunctivitis, but like other topical antiinfective preparations, benefits are limited.

2.Orally for:

(a) Preparation of bowel before surgery: (3 doses of 1.0 g along with metronidazole 0.5 g on day before surgery) may reduce postoperative infections.

(b) Hepatic coma: Normally NH3 is produced by colonic bacteria. This is absorbed and converted to urea by liver. In severe hepatic failure, detoxication of NH3 does not occur, blood NH3 levels rise and produce encephalopathy. Neomycin, by suppressing intestinal flora, diminishes NH3 production and lowers its blood level; clinical improvement is seen within 2–3 days. However, because of toxic potential it is infrequently used for this purpose; Lactulose (see p. 676) is preferred.

Adverse effects Applied topically neomycin has low sensitizing potential. However, rashes do occur.

Oral neomycin has a damaging effect on intestinal villi. Prolonged treatment can induce malabsorption syndrome with diarrhoea and steatorrhoea. It can decrease the absorption of digoxin and many other drugs, as well as bile acids.

Due to marked suppression of gut flora, superinfection by Candida can occur.

Small amounts that are absorbed from the gut or topical sites are excreted unchanged by kidney. This may accumulate in patients with renal insufficiency—cause further kidney damage and ototoxicity. Neomycin is contraindicated if renal function is impaired.

Applied to serous cavities (peritoneum), it can cause apnoea due to muscle paralysing action.

Neomycin containing antidiarrhoeal formulations are banned in India.

Framycetin

Obtained from S. lavendulae, it is very similar to neomycin. It is too toxic for systemic administration and is used topically on skin, eye, ear in the same manner as neomycin.

SOFRAMYCIN, FRAMYGEN 1% skin cream, 0.5% eye drops or oint.

Paromomycin

Chemically related to neomycin, this aminoglycoside antibiotic has pronounced activity against many protozoan parasites, including

E. histolytica, Giardia lamblia, Trichomonas vaginalis, Cryptosporidium and Leishmania, in addition to many bacteria sensitive to neomycin. Like other aminoglycosides, it is not absorbed from the gut. An oral formulation was marketed in many countries, including India, in the 1960s for treatment of intestinal amoebiasis and giardiasis, but was soon discontinued when metronidazole gained popularity. Recently, it has been reintroduced and is described in Ch. 60. For its antibacterial activity in the gut, it can be used as an alternative to neomycin for hepatic encephalopathy. Parenterally, it is being used for visceral leishmaniasis (see Ch. 60).

Dose: Oral 500 mg TDS (25–30 mg/kg/day) PAROMYCIN, HUMATIN 250 mg cap.

)PROBLEM DIRECTED STUDY

53.1A 75-year-old unconscious male patient of cerebral stroke is maintained on ventilator

in the intensive care unit of the hospital. On the 4th day he developed fever, and the total leucocyte count rose to 14000/μL, along with signs of chest infection. A sample of bronchial aspirate is sent for bacteriological tests, and it is decided to institute empirical treatment with cefotaxime and gentamicin. His body weight is 60 kg and creatinine clearance is estimated to be 50 ml/min.

(a) What should be the appropriate dose and dosing regimen for gentamicin and cefotaxime for this patient?

(see Appendix-1 for solution)

53 CHAPTER

MACROLIDE ANTIBIOTICS

These are antibiotics having a macrocyclic lactone ring with attached sugars. Erythromycin is the first member discovered in the 1950s,

Roxithromycin, Clarithromycin and Azithromycin are the later additions.

ERYTHROMYCIN

It was isolated from Streptomyces erythreus in 1952. Since then it has been widely employed, mainly as alternative to penicillin. Water solubility of erythromycin is limited, and the solution remains stable only when kept in cold.

Mechanism of action Erythromycin is bacteriostatic at low but cidal (for certain bacteria only) at high concentrations. Cidal action depends on the organism concerned and its rate of multiplication. Sensitive gram-positive bacteria accumulate erythromycin intracellularly by active transport which is responsible for their high susceptibility to this antibiotic. Activity is enhanced several fold in alkaline medium, because the nonionized (penetrable) form of the drug is favoured at higher pH.

Erythromycin acts by inhibiting bacterial protein synthesis. It combines with 50S ribosome subunits and interferes with ‘translocation’ (see Fig. 52.1). After peptide bond formation between the newly attached amino acid and the nacent peptide chain at the acceptor (A) site, the elongated peptide is translocated back to the peptidyl (P) site, making the A site available for next aminoacyl tRNA attachment. This is prevented by erythromycin and the ribosome fails to move along the mRNA to expose the next codon. As an indirect consequence, peptide chain may

be prematurely terminated: synthesis of larger proteins is especifically suppressed.

Antimicrobial spectrum It is narrow, includes mostly gram-positive and a few gramnegative bacteria, and overlaps considerably with that of penicillin G. Erythromycin is highly active against Str. pyogenes and Str. pneumoniae, N. gonorrhoeae, Clostridia, C. diphtheriae and

Listeria, but penicillin-resistant Staphylococci and Streptococci are now resistant to erythromycin also.

In addition, Campylobacter, Legionella, Branhamella catarrhalis, Gardnerella vaginalis and Mycoplasma, that are not affected by penicillin, are highly sensitive to erythromycin. Few others, including H. ducreyi, H. influenzae, B. pertussis, Chlamydia trachomatis, Str. viridans, N. meningitidis and Rickettsiae are moderately sensitive. Enterobacteriaceae, other gram-negative bacilli and B. fragilis are not inhibited.

Resistance All cocci readily develop resistance to erythromycin, mostly by acquiring the capacity to pump it out. Resistant Enterobacteriaceae have been found to produce an erythromycin esterase. Alteration in the ribosomal binding site for erythromycin by a plasmid encoded methylase enzyme is an important mechanism of resistance in gram-positive bacteria. All the above types of resistance are plasmid mediated. Change in the 50S ribosome by chromosomal mutation reducing macrolide binding affinity occurs in some gram-positive bacteria.

Bacteria that develop resistance to erythromycin are cross resistant to other macrolides as well. Cross resistance with clindamycin and

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of rheumatic fever and SABE. However, many bacteria resistant to penicillin are also resistant to erythromycin.

2.Diphtheria: For acute stage as well as for carriers—7 day treatment is recommended. Some prefer it over penicillin. Antitoxin is the primary treatment.

3.Tetanus: as an adjuvant to antitoxin, toxoid therapy.

4.Syphilis and gonorrhoea: only if other alternative drugs, including tetracyclines also cannot be used: relapse rates are higher.

5.Leptospirosis: 250 mg 6 hourly for 7 days

in patients allergic to penicillins.

B. As a first choice drug for

1.Atypical pneumonia caused by Mycoplasma pneumoniae: rate of recovery is hastened.

2.Whooping cough: a 1–2 week course of erythromycin is the most effective treatment for eradicating B. pertussis from upper respiratory tract. However, effect on the symptoms depends on the stage of disease when treatment is started.

(a)Prophylactic: during the 10 day incubation period—disease is prevented.

(b)Catarrhal stage: which lasts for about a week—erythromycin may abort the next stage or reduce its duration and severity.

(c)Paroxysmal stage: lasting 2–4 weeks— no effect on the duration and severity of ’croup’ despite eradication of the causative organism.

(d)Convalescent stage: during which ‘croup’ gradually resolves (4–12 weeks)—is not modified.

Azithromycin, clarithromycin, and chloramphenicol are the alternative antimicrobials. Cough sedatives are not very effective. Corticosteroids may reduce the duration of paroxysmal stage but increase the risk of superinfections and carrier stage; they should be reserved for severe cases only. Adrenergic β2 stimulants may reduce the severity of paroxysms, and are more useful in infants.

3. Chancroid : erythromycin 2 g/day for 7 days is one of the first line drugs, as effective as single dose azithromycin or ceftriaxone (see p. 763).

C. As a second choice drug in

1.Campylobacter enteritis: duration of diarrhoea and presence of organisms in stools is reduced. However, fluoroquinolones are superior.

2.Legionnaires’ pneumonia: 3 week erythromycin treatment is effective, but azithromycin/ciprofloxacin are preferred.

3.Chlamydia trachomatis infection of urogenital tract: erythromycin 500 mg 6 hourly for 7 days is an effective alternative to single dose azithromycin (see p. 763).

4.Penicillin-resistant Staphylococcal infections: its value has reduced due to emergence of erythromycin resistance as well. It is not effective against MRSA.

NEWER MACROLIDES

In an attempt to overcome the limitations of erythromycin like narrow spectrum, gastric intolerance, gastric acid lability, low oral bioavailability, poor tissue penetration and short half-life, a number of semisynthetic macrolides have been produced, of which roxithromycin, clarithromycin and azithromycin have been marketed.

Roxithromycin It is a semisynthetic longeracting acid-stable macrolide whose antimicrobial spectrum resembles closely with that of erythromycin. It is more potent against Branh. catarrhalis, Gard. vaginalis and Legionella but less potent against B. pertussis. Good enteral absorption and an average plasma t½ of 12 hr making it suitable for twice daily dosing, as well as better gastric tolerability are its desirable features.

Though its affinity for cytochrome P450 is lower, drug interactions with terfenadine, cisapride and others are not ruled out. Thus, it is an alternative to erythromycin for respiratory, ENT, skin and soft tissue and genital tract infections with similar efficacy.

Dose: 150–300 mg BD 30 min before meals, children 2.5–5 mg/kg BD.

ROXID, ROXIBID, RULIDE 150, 300 mg tab, 50 mg kid tab, 50 mg /5 ml liquid; ROXEM 50 mg kid tab, 150 mg tab.

Clarithromycin The antimicrobial spectrum of clarithromycin is similar to erythromycin; in addition, it includes Mycobact. avium complex (MAC), other atypical mycobacteria, Mycobact. leprae and some anaerobes but not Bact. fragilis.

It is more active against Helicobacter pylori,

Moraxella, Legionella, Mycoplasma pneumoniae and sensitve strains of gram-positive bacteria. However, bacteria that have developed resistance to erythromycin are resistant to clarithromycin also.

Clarithromycin is more acid-stable than erythromycin, and is rapidly absorbed; oral bioavailability is ~50% due to first pass metabolism; food delays but does not decrease absorption. It has slightly larger tissue distribution than erythromycin and is metabolized by saturation kinetics—t½ is prolonged from 3–6 hours at lower doses to 6–9 hours at higher doses. An active metabolite is produced. About 1/3 of an oral dose is excreted unchanged in urine, but no dose modification is needed in liver disease or in mild-to-moderate kidney failure.

Clarithromycin is indicated in upper and lower respiratory tract infections, sinusitis, otitis media, whooping cough, atypical pneumonia, skin and skin structure infections due to Strep. pyogenes and some Staph. aureus. Used as a component of triple drug regimen (see p. 657) it eradicates H. pylori in 1–2 weeks. It is a first line drug in combination regimens for MAC infection in AIDS patients and a second line drug for other atypical mycobacterial diseases as well as leprosy.

Dose: 250 mg BD for 7 days; severe cases 500 mg BD up to 14 days.

CLARIBID 250, 500 mg tabs, 250 mg/5 ml dry syr; CLARIMAC 250, 500 mg tabs; SYNCLAR 250 mg tab, 125 mg/5 ml dry syr.

Side effects of clarithromycin are similar to those of erythromycin, but gastric tolerance is better. High doses can cause reversible hearing loss. Few cases of pseudomembranous enterocolitis, hepatic dysfunction or rhabdomyolysis are reported. Its safety in pregnancy and lactation is not known. It inhibits CYP3A4, and the drug interaction potential is similar to erythromycin.

Azithromycin This azalide congener of erythromycin has an expanded spectrum, improved pharmacokinetics, better tolerability and drug interaction profiles. It is more active than

other macrolides against H. influenzae, but less active against gram-positive cocci. High activity is exerted on respiratory pathogens—Myco- plasma, Chlamydia pneumoniae, Legionella, Moraxella and on others like Campylobacter. Ch. trachomatis, H. ducreyi, Calymm. granulomatis, N. gonorrhoeae. However, it is not active against erythromycin-resistant bacteria. Penicillinase producing Staph. aureus are inhibited but not MRSA. Good activity is noted against MAC.

The remarkable pharmacokinetic properties are acid-stability, rapid oral absorption (from empty stomach), larger tissue distribution and intracellular penetration. Concentration in most tissues exceeds that in plasma. Particularly high concentrations are attained inside macrophages and fibroblasts; volume of distribution is ~30 L/kg. Slow release from the intracellular sites contributes to its long terminal t½ of >50 hr. It is largely excreted unchanged in bile, renal excretion is ~ 10%.

Because of higher efficacy, better gastric tolerance and convenient once a day dosing, azithromycin is now preferred over erythromycin as first choice drug for infections such as:

(a)Legionnaires’ pneumonia: 500 mg OD oral/ i.v. for 2 weeks. Erythromycin or a FQ are the alternatives.

(b)Chlamydia trachomatis: nonspecific urethritis and genital infections in both men and women —1 g single dose is curative, while 3 weekly doses are required for lymphogranuloma venereum (see p. 763). It is also the drug of choice for chlamydial pneumonia and is being preferred over tetracycline for trachoma in the eye.

(c). Donovanosis caused by Calymmatobacterium granulomatis: 500 mg OD for 7 days or 1.0 g weekly for 4 weeks is as effective as doxycycline.

(d)Chancroid and PPNG urethritis: single 1.0 g dose is highly curative (see p. 763).

The other indications of azithromycin are pharyngitis, tonsillitis, sinusitis, otitis media, pneumonias, acute exacerbations of chronic

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bronchitis, streptococcal and some staphylococcal skin and soft tissue infections. In combination with at least one other drug it is effective in the prophylaxis and treatment of MAC in AIDS patients. Other potential uses are in multidrug resistant typhoid fever in patients allergic to cephalosporins; and in toxoplasmosis.

Dose: 500 mg once daily 1 hour before or 2 hours after food (food decreases bioavailability); (children above 6 month—10 mg/kg/day) for 3 days is sufficient for most infections.

AZITHRAL 250, 500 mg cap and 250 mg per 5 ml dry syr; AZIWOK 250 mg cap, 100 mg kid tab, 100 mg/5 ml and 200 mg/ 5 ml susp.AZIWIN 100, 250, 500 mg tab, 200 mg/5 ml liq. Also AZITHRAL 500 mg inj.

Side effects are mild gastric upset, abdominal pain (less than erythromycin), headache and dizziness. Azithromycin has been found not to affect hepatic CYP3A4 enzyme. Interaction with theophylline, carbamazepine, warfarin, terfenadine and cisapride is not likely, but caution may be exercised.

Spiramycin This macrolide antibiotic, though available for more than a decade, has been employed only sporadically. It resembles erythromycin in spectrum of activity and properties. Distinctively, it has been found to limit risk of transplacental transmission of Toxoplasma gondii infection. Its specific utility is for toxoplasmosis and recurrent abortion in pregnant women; 3 week courses of 3 MU 2–3 times a day are repeated after 2 week gaps till delivery. Other indications are similar to erythromycin, for which 6 MU/day is given for 5 days. Side effects are gastric irritation, nausea, diarrhoea and rashes.

ROVAMYCIN 1.5 MU, 3 MU tabs, 0.375 MU/ 5 ml susp.

LINCOSAMIDE ANTIBIOTICS Clindamycin

This potent lincosamide antibiotic is similar in mechanism of action (inhibits protein synthesis by binding to 50S ribosome) and spectrum of activity to erythromycin with which it exhibits partial cross resistance. Modification of the ribosomal binding site by the constitutive methylase enzyme confirs resistance to both, but not the inducible enzyme. Antibiotic efflux is not an important mechanism of clindamycin resistance. Clindamycin inhibits most grampositive cocci (including most species of streptococci, penicillinase producing Staph., but

not MRSA), C. diphtheriae, Nocardia, Actinomyces, Toxoplasma and has slow action on Plasmodia. However, the distinctive feature is its high activity against a variety of anaerobes, especially Bact. fragilis. Aerobic gram-negative bacilli, spirochetes, Chlamydia, Mycoplasma and Rickettsia are not affected.

Oral absorption of clindamycin is good. It penetrates into most skeletal and soft tissues, butnotinbrainandCSF;accumulatesinneutrophils and macrophages. It is largely metabolized and metabolites are excreted in urine and bile. The t½ is 3 hr.

Side effects are rashes, urticaria, abdominal pain, but the major problem is diarrhoea and pseudomembranous enterocolitis due to Clostridium difficile superinfection which is potentially fatal. The drug should be promptly stopped and oral metronidazole (alternatively vancomycin) given to treat it. Thrombophlebitis of the injected vein can occur on i.v. administration.

Because of the potential toxicity, use of clindamycin is restricted to anaerobic and mixed infections, especially those involving Bact. fragilis causing abdominal, pelvic and lung abscesses. It is a first line drug for these conditions, and is generally combined with an aminoglycoside or a cephalosporin. Metronidazole and chloramphenicol are the alternatives to clindamycin for covering the anaerobes. Skin and soft tissue infections in patients allergic to penicillins can be treated with clindamycin. Anaerobic streptococcal and Cl. perfringens infections, especially those involving bone and joints respond well. It has also been employed for prophylaxis of endocarditis in penicillin allergic patients with valvular defects who undergo dental surgery, as well as to prevent surgical site infection in colorectal/pelvic surgery.

In AIDS patients, it has been combined with pyrimethamine for toxoplasmosis and with primaquine for Pneumocystis jiroveci pneumonia. It is an alternative to doxycycline for supplementing quinine/artesunate in treating multidrug resistant falciparum malaria. Topically it is used for infected acne vulgaris.

Clindamycin, erythromycin and chloramphenicol can exhibit mutual antagonism, probably because their ribosomal binding sites are proximal; binding of one hinders access of the other to its target site. Clindamycin slightly potentiates neuromuscular blockers.

Dose: 150–300 mg (children 3–6 mg/kg) QID oral; 200–600 mg i.v. 8 hourly; DALCAP 150 mg cap; CLINCIN 150, 300 mg cap; DALCIN, DALCINEX 150, 300 mg cap, 300 mg/2 ml and 600 mg/ 4 ml inj.ACNESOL, CLINDAC-A1% topical solution and gel.

Lincomycin

It is the forerunner of clindamycin; has similar antibacterial and toxic properties, but is less potent and produces a higher incidence of diarrhoea and colitis—deaths have occurred. Thus, it has been largely replaced by clindamycin. It is absorbed orally and excreted mainly in bile; plasma t½ 5 hrs. Dose: 500 mg TDS-QID oral; 600 mg i.m. or by i.v. infusion 6–12 hrly.

LINCOCIN 500 mg cap, 600 mg/2 ml inj; LYNX 250, 500 mg cap, 125 mg/5 ml syr, 300 mg/ml inj in 1, 2 ml amp.

GLYCOPEPTIDE ANTIBIOTICS

Vancomycin

It is a glycopeptide antibiotic discovered in 1956 as a penicillin substitute which assumed special significance due to efficacy against MRSA,

Strep. viridans, Enterococcus and Cl. difficile. Bactericidal action is exerted on gram-positive cocci, Neisseria, Clostridia and diphtheroids. However, in hospitals where it has been extensively used for surgical prophylaxis, etc., vancomycin-resistant Staph. aureus (VRSA) and vancomycin-resistant Enterococcus (VRE) have emerged. These nosocomial bacteria are resistant to methicillin and most other antibiotics as well. Gram-negative bacilli are inherently non-respon- sive to vancomycin.

Vancomycin acts by inhibiting bacterial cell wall synthesis. It binds to the terminal dipeptide ‘D-ala-D-ala’ sequence of peptidoglycan units— prevents its release from the bactoprenol lipid carrier so that assembly of the units at the cell membrane and their cross linking to form the cell wall cannot take place (see Fig. 51.2). Enterococcal resistance to vancomycin is due to a plasmid mediated alteration of the dipeptide target site, reducing its affinity for vancomycin.

Vancomycin is not absorbed orally. After i.v. administration, it is widely distributed, penetrates serous cavities, inflamed meninges and is excreted mainly unchanged by glomerular filtration with a t½ of 6 hours. Dose reduction is needed in renal insufficiency.

Toxicity: Systemic toxicity of vancomycin is high. It can cause plasma concentration-depen- dent nerve deafness which may be permanent. Kidney damage is also dose-related. Other otoand nephrotoxic drugs like aminoglycosides must be very carefully administered when vancomycin is being used. Skin allergy and fall in BP during i.v. injection can occur. Vancomycin has the potential to release histamine by direct action on mast cells. Rapid i.v. injection has caused chills, fever, urticaria and intense flushing— called ‘Red man syndrome’.

Uses: Given orally (125–500 mg 6 hourly), it is the second choice drug to metronidazole for antibiotic associated pseudomembranous enterocolitis caused by C. difficile. Staphylococcal enterocolitis is another indication of oral vancomycin.

Systemic use (500 mg 6 hourly or 1 g 12 hourly infused i.v. over 1 hr) is restricted to serious MRSA infections for which it is the most effective drug, and as a penicillin substitute (in allergic patients) for enterococcal endocarditis along with gentamicin. It is an alternative drug for serious skin, soft tissue and skeletal infections in which gram-positive bacteria are mostly causative. For empirical therapy of bacterial meningitis, i.v. vancomycin is usually combined with i.v. ceftriaxone/cefotaxime. It is also used in dialysis patients and those undergoing cancer chemotherapy. Penicillin-resistant pneumococcal infections and infection caused by diphtheroids respond very well to vancomycin.

Vancomycin is the preferred surgical prophylactic in MRSA prevalent areas and in penicillin allergic patients.

VANCOCIN-CP,VANCOGEN, VANCORID-CP500 mg/vial inj; VANCOLED 0.5, 1.0 g inj. VANCOMYCIN 500 mg tab, VANLID 250 mg cap, 500 mg/vial inj.

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Teicoplanin

This newer glycopeptide antibiotic is a mixture of 6 similar compounds, active against grampositive bacteria only. The mechanism of action and spectrum of activity is similar to vancomycin. Notable features are:

•It is more active than vancomycin against enterococci, and equally active against MRSA.

•Some VRE but not VRSA are susceptible to teicoplanin.

•It can be injected i.m. as well; is largely excreted unchanged by kidney; dose needs to be reduced in renal insufficiency; has a very long t½ (3–4 days).

•Toxicity is less than vancomycin; adverse effects are rashes, fever, granulocytopenia and occasionally hearing loss. Reactions due to histamine release are rare (1 in 2500).

Teicoplanin is indicated in enterococcal endocarditis (along with gentamicin); MRSA and penicillin resistant streptococcal infections, osteomyelitis and as alternative to vancomycin for surgical prophylaxis, etc.

Dose: 400 mg first day—then 200 mg daily i.v. or i.m.; severe infection 400 mg × 3 doses 12 hourly—then 400 mg daily. TARGOCID, TECOPLAN, TECOCIN 200, 400 mg per vial inj. for reconstitution.

OXAZOLIDINONE

Linezolid

This is the first member of a new class of synthetic AMAs ‘Oxazolidinones’ useful in the treatment of resistant gram-positive coccal (aerobic and anaerobic) and bacillary infections. It is active against MRSA and some VRSA, VRE, penicillin-resistant Strep. pyogenes, Strep. viridans and Strep. pneumoniae, M. tuberculosis, Corynebacterium, Listeria, Clostridia and Bact. fragilis. It is primarily bacteriostatic, but can exert cidal action against some streptococci, pneumococci and B. fragilis. Gramnegative bacteria are not affected.

Linezolid inhibits bacterial protein synthesis by acting at an early step and a site different from that of other AMAs. It binds to the 23S fraction

(P site) of the 50S ribosome and interferes with formation of the ternary N-formylmethionine- tRNA (tRNAfMet) -70S initiation complex. Binding of linezolid distorts the tRNA binding site overlapping both 50S and 30S ribosomal subunits and stops protein synthesis before it starts. As such, there is no cross resistance with any other class of AMAs. Linezolid resistance due to mutation of 23S ribosomal RNA has been detected among enterococci.

Linezolid is rapidly and completely absorbed orally, partly metabolized nonenzymatically and excreted in urine. Plasma t½ is 5 hrs. Dose modification has not been necessary in renal insufficiency.

Linezolid given orally or i.v. is used for uncomplicated and complicated skin and soft tissue infections, community and hospitalacquired pneumonias, bacteraemias and other drug-resistant gram-positive infections with 83–94% cure rates. However, in order to prevent emergence of resistance to this valuable drug, use should be restricted to serious hospitalacquired pneumonias, febrile neutropenia, wound infections and others caused by multidrugresistant gram-positive bacteria such as VRE, vancomycin resistant-MRSA, multi-resistant S. pneumoniae, etc. Being bacteriostatic, it is not suitable for treatment of enterococcal endocarditis.

Dose: 600 mg BD, oral/ i.v.; LIZOLID 600 mg tab; LINOX, LINOSPAN 600 mg tab, 600 mg/300 ml i.v. infusion.

Side effects to linezolid have been few; mostly mild abdominal pain, nausea, taste disturbance and diarrhoea. Occasionally, rash, pruritus, headache, oral/vaginal candidiasis have been reported. Neutropenia, anaemia and thrombocytopenia are infrequent and mostly associated with prolonged use. Optic neuropathy has occurred after linezolid is given for >4 weeks. Because linezolid is a MAO inhibitor, interactions with adrenergic/serotonergic drugs (SSRIs, etc.) and excess dietary tyramine are expected. No cytochrome P450 enzyme related interactions seem likely.

MISCELLANEOUS ANTIBIOTICS

Spectinomycin It is a chemically distinct (aminocyclitol), narrow spectrum, bacteriostatic antibiotic which inhibits a limited number of gram-negative bacteria, notably Neisseria gonorrhoeae. It acts by binding to 30S ribosome and inhibiting bacterial protein synthesis, but the action is distinct from that of aminoglycosides. The single approved indication of spectinomycin is treatment of drug resistant gonorrhoea, or when the first line drugs (β-lactams/macrolides, etc.) can not be used due to allergy or other contraindication.

Dose: 2.0 g i.m. single dose; for less responsive cases 4.0 g (2.0 g at 2 sites).

MYSPEC, TROBICIN 2.0 g/vial inj.

The single dose is well tolerated; chills, fever and urticaria are occasional side effects. Repeated doses may cause

anaemia, renal and hepatic impairment.

Quinupristin/Dalfopristin It is a combination of two semisynthetic pristinamycin antibiotics which together exert synergistic inhibition of bacterial protein synthesis. It is active against most gram-positive cocci including MRSA, some VRSA and some VRE; as well as certain Neisseria, Legionella and Chlamydia pneumoniae. The combination is bactericidal against strepto and staphylococci but bacteriostatic against

E. faecium.

It is being used for serious nosocomial MRSA, VRE and other resistant gram-positive infections.

Mupirocin This topically used antibiotic obtained from a species of Pseudomonas is active mainly against gram-positive bacteria, including Strep. pyogenes (penicillin sensitive/ resistant), Staph aureus. MRSA, etc. It inhibits bacterial protein synthesis by blocking the production of t-RNA for isoleucin. As such, no cross resistance with any other antibiotic is seen. Though primarily bacteriostatic, high concentrations applied topically may be bactericidal. It is indicated in furunculosis, folliculitis, impetigo, infected insect bites and small wounds. Local itching, irritation and redness may occur.

BACTROBAN, MUPIN, T-BACT 2% oint. for topical application thrice daily.

Fusidic acid It is a narrow spectrum steroidal antibiotic, blocks bacterial protein synthesis. It is active against penicillinase producing Staphylococci and few other grampositive bacteria. It is used only topically for boils, folliculitis, sycosis barbae and other cutaneous infections.

FUCIDIN-L, FUCIBACT, FUSIDERM; 2% oint. and cream.

POLYPEPTIDE ANTIBIOTICS

These are low molecular weight cationic polypeptide antibiotics. All are powerful bactericidal agents, but not used systemically due to toxicity. All are produced by bacteria. Clinically used ones are:

Polymyxin B Colistin Bacitracin

Polymyxin B and Colistin Polymyxin and colistin were obtained in the late 1940s from Bacillus polymyxa and B. colistinus respectively. They are active against gram-negative bacteria only; all except Proteus, Serratia and Neisseria are inhibited. Both have very similar range of activity, but colistin is more potent on Pseudomonas, Salmonella and Shigella.

Mechanism of action They are rapidly acting bactericidal agents; have a detergent-like action on the cell membrane. They have high affinity for phospholipids: the peptide molecules (or their aggregates) orient between the phospholipid and protein films in gram-negative bacterial cell membrane causing membrane distortion or pseudopore formation. As a result ions, amino acids, etc. leak out. Sensitive bacteria take up more of the antibiotic. They may also inactivate the bacterial endotoxin.

They exhibit synergism with many other AMAs by improving their penetration into the bacterial cell.

Resistance Resistance to these antibiotics has never been a problem. There is no cross resistance with any other AMA.

Adverse effects Little or no absorption occurs from oral route or even from denuded skin (burn, ulcers). Applied topically, they are safe—no systemic effect or sensitization occurs. A rash is rare.

•Given orally, side effects are limited to the g.i.t.—occasional nausea, vomiting, diarrhoea.

•Systemic toxicity of these drugs (when injected) is high: flushing and paresthesias (due to liberation of histamine from mast cells), marked kidney damage, neurological disturbances, neuromuscular blockade.

Preparation and dose

Polymyxin B: (1 mg = 10,000 U)

NEOSPORIN POWDER: 5000 U with neomycin sulf. 3400 U and bacitracin 400 U per g.

NEOSPORIN EYE DROPS: 5000 U with neomycin sulf. 1700 U and gramicidin 0.25 mg per ml.

NEOSPORIN-HEARDROPS:10,000Uwithneomycinsulf.3400 U and hydrocortisone 10 mg per ml.

Colistin sulfate: 25–100 mg TDS oral

WALAMYCIN 12.5 mg (25000 i.u.) per 5 ml dry syr, COLISTOP 12.5 mg/5 ml and 25 mg/5 ml dry syr.

Uses

(a)Topically Usually in combination with other antimicrobials for skin infections, burns, otitis externa, conjunctivitis, corneal ulcer—caused by gram-negative bacteria including

Pseudomonas.

(b)Orally Gram-negative bacillary (E. coli, Salmonella, Shigella) diarrhoeas, especially in infants and children; Pseudomonas superinfection enteritis.

Bacitracin It is one of the earliest discovered antibiotics from a strain of Bacillus subtilis. In contrast to polymyxin,

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it is active mainly against gram-positive organisms (both cocci and bacilli). Neisseria, H. influenzae and few other bacteria are also affected.

It acts by inhibiting cell wall synthesis at a step earlier than that inhibited by penicillin. Subsequently, it increases the efflux of ions by binding to cell membrane. It is bactericidal.

Bacitracin is not absorbed orally. It is not given parenterally because of high toxicity, especially to the kidney. Use is restricted to topical application for infected wounds, ulcers, eye infections—generally in combination with neomycin, polymyxin, etc.

NEBASULF Bacitracin 250 U + neomycin 5 mg + sulfacetamide 60 mg/g powder, skin oint, eye oint; in NEOSPORIN 400 U/g powder (1 U = 26 µg).

It does not penetrate intact skin, therefore, is of little value in furunculosis, boils, carbuncles, etc.

URINARY ANTISEPTICS

Some orally administered AMAs attain antibacterial concentration only in urine, with little or no systemic antibacterial effect. Like many other drugs, they are concentrated in the kidney tubules, and are useful mainly in lower urinary tract infection. They have been called urinary antiseptics because this may be considered as a form of local therapy. Nitrofurantoin and methenamine are two such agents; infrequently used now. Nalidixic acid (see p. 709) can also be considered to be a urinary antiseptic.

Nitrofurantoin

It is primarily bacteriostatic, but may be cidal at higher concentrations and in acidic urine. Its activity is enhanced at lower pH. Many gram-negative bacteria were susceptible, but due to development of resistance, activity is now restricted largely to E. coli. Resistance to nitrofurantoin does not develop during continued therapy. No cross resistance with any other AMA is known, though it antagonizes the bactericidal action of nalidixic acid. Susceptible bacteria enzymatically reduce nitrofurantoin to generate reactive intermediates which damage DNA.

Pharmacokinetics Nitrofurantoin is well absorbed orally; rapidly metabolized in liver and other tissues; less than half is excreted unchanged in urine; plasma t½ is 30–60 min. Antibacterial concentrations are not attained in blood or tissues. Probenecid inhibits its tubular secretion and reduces the concentration attained in urine—may interfere with its urinary antiseptic action. Renal excretion is reduced in azotaemic patients; effective concentrations may not be reached in the urine, while toxicity increases. As such, it is contraindicated in renal failure; also during pregnancy and in neonates.

Adverse effects Commonest is gastrointestinal intole- rance—nausea, epigastric pain and diarrhoea.

An acute reaction with chills, fever and leucopenia occurs occasionally.

Peripheral neuritis and other neurological effects are reported with long-term use. Haemolytic anaemia is rare, except in G-6-PD deficiency. Liver damage and a pulmonary reaction with fibrosis on chronic use are infrequent events.

Urine of patients taking nitrofurantoin turns dark brown on exposure to air.

Use The only indication for nitrofurantoin is uncomplicated lower urinary tract infection not associated with prostatitis, but it is infrequently used now. Acute infections due to E. coli can be treated with 50–100 mg TDS (5–7 mg/kg/day) given for 5–10 days. These doses should not be used for > 2 weeks at a time. Suppressive long-term treatment has been successful with 50 mg BD or 100 mg at bed time. This dose can also be employed for prophylaxis of urinary tract infection following catheterization or instrumentation of the lower urinary tract and in women with recurrent cystitis.

FURADANTIN 50, 100 mg tab, URINIF 100 mg tab.. NEPHROGESIC: Nitrofurantoin 50 mg + phenazopyridine 100 mg tab.

Methenamine (Hexamine)

It is hexamethylene-tetramine, which is inactive as such; decomposes slowly in acidic urine to release formaldehyde which inhibits all bacteria. This drug exerts no antimicrobial activity in blood and tissues, including kidney parenchyma. Acidic urine is essential for its action; urinary pH must be kept below 5.5 by administering an organic acid which is excreted as such, e.g. mandelic acid or hippuric acid or ascorbic acid.

Methenamine is administered in enteric coated tablets to protect it from decomposing in gastric juice. Mandelic acid, given as methenamine mandelate, is excreted in urine →lowers urinary pH and promotes decomposition of methenamine. Lower urinary pH itself disfavours growth of urinary pathogens.

MANDELAMINE : Methenamine mandelate 0.5 g, 1 g tab: 1 g TDS or QID with fluid restriction (daily urine volume between 1–1.5 L) to ensure adequate concentration of formaldehyde in urine.

It is not an effective drug for acute urinary tract infections or for catheterization prophylaxis. Its use is restricted to chronic, resistant type of urinary tract infections, not involving kidney substance. Resistance to formaldehyde does not occur, but methenamine is rarely used now.

Adverse effects Gastritis can occur due to release of formaldehyde in stomach—patient compliance is poor due to this. Chemical cystitis and haematuria may develop with high doses given for long periods. CNS symptoms are produced occasionally.

URINARY ANALGESIC

Phenazopyridine It is an orange dye which exerts analgesic action in the urinary tract and affords symptomatic relief of burning sensation, dysuria and urgency due to cystitis. It does not have antibacterial property. Side effects are nausea and epigastric pain.

Dose: 200–400 mg TDS: PYRIDIUM 200 mg tab.

TREATMENT OF URINARY TRACT INFECTIONS

The general principles of use of AMAs for urinary tract infections (UTIs) remain the same as for any other infection. Some specific considerations are highlighted below.

Most UTIs are caused by gram-negative bacteria, especially coliforms. Majority of acute infections involve a single organism (commonest is E. coli); chronic and recurrent infections may be mixed infections. Acute infections are largely self limiting; high urine flow rates with frequent bladder voiding may suffice. Many single dose antimicrobial treatments have been successfully tried, but a three day regimen is considered optimal for lower UTIs. Upper UTIs require more aggressive and longer treatment. In any case, treatment for more than 2 weeks is seldom warranted.

Bacteriological investigations are very important to direct the choice of drug. Though, treatment may not wait till report comes, urine sample must be collected for bacteriology before commencing therapy. Most AMAs attain high concentration in urine, smaller than usual doses may be effective in lower UTIs, because antibacterial action in urine is sufficient, mucosa takes care of itself. In upper UTI (pyelonephritis) antimicrobial activity in kidney tissue is needed. Therefore, doses are similar to those for any systemic infection.

The least toxic and cheaper AMA should be used, just long enough to eradicate the pathogen. It is advisable to select a drug which does not disrupt normal gut and perineal flora. If recurrences are frequent, chronic suppressive treatment with cotrimoxazole, nitrofurantoin, methenamine, cephalexin or norfloxacin may be given.

The commonly used antimicrobial regimens for empirical therapy of uncomplicated acute UTI are given in the box.

Antimicrobial regimens for acute UTI (all given orally for 3–5 days)*

1.Norfloxacin 400 mg 12 hourly

2.Ciprofloxacin 250–500 mg 12 hourly

3.Ofloxacin 200–400 mg 12 hourly

4.Cotrimoxazole 960 mg 12 hourly

5.Cephalexin 250–500 mg 6 hourly

6.Cefpodoxime proxetil 200 mg 12 hourly

7. Amoxicillin + clavulanic acid (500 + 125 mg)

8 hourly

8.Nitrofurantoin 50 mg 8 hourly or 100 mg 12 hourly × 5–7 days

*For upper UTI (pyelonephritis), the same drugs may be given for 2–3 weeks. Nitrofurantoin is not suitable for pyelonephritis.

The status of AMAs (other than urinary antiseptics) in urinary tract infections is summarized below:

1.Sulfonamides Dependability in acute UTIs has decreased; they are not used now as single drug. May occasionally be employed for suppressive and prophylactic therapy.

2.Cotrimoxazole (see p. 708) Though response rate and use have declined, it may be employed empirically in acute UTI without bacteriological data, because majority of urinary pathogens, including Chlamydia trachomatis, are covered by cotrimoxazole. Given once daily at bed time cotrimoxazole 480 mg is often used for prophylaxis of recurrent cystitis in women, as well as in catheterized patients. It should not be used to treat UTI during pregnancy.

3.Quinolones (see p. 711) The first generation FQs, especially norfloxacin and ciprofloxacin are highly effective and currently the most popular drugs, because of potent action against gramnegative bacilli and low cost. Nalidixic acid is seldom employed. However, to preserve their efficacy, use should be restricted. FQs are particularly valuable in complicated cases, those

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with prostatitis or indwelling catheters and for bacteria resistant to cotrimoxazole/ampicillin. Norfloxacin given for upto 12 weeks may achieve cure in chronic UTI. The FQs should not be given to pregnant women.

4. Ampicillin/Amoxicillin (see p. 722) Frequently used in the past as first choice drug for initial treatment of acute infections without bacteriological data, but higher failure and relapse rates have made them unreliable for empirical therapy. Many E. coli strains are now ampicillin-resistant. Amoxicillin + clavulanic acid is more frequently employed. Parenteral coamoxiclav is often combined with gentamicin for initial treatment of acute pyelonephritis.

5.Cloxacillin Use is restricted to penicillinase producing staphylococcal infection, which is uncommon in urinary tract.

6.Piperacillin/Carbenicillin Only in serious Pseudomonas infection in patients with indwelling catheters or chronic urinary obstructin (prostatic hypertrophy, calculi), and in hospitalized patients on the basis of in vitro sensitivity.

7.Cephalosporins Use is increasing, espe-

cially in women with nosocomial Klebsiella and Proteus infections. They should normally be employed only on the basis of sensitivity report, but empirical use for community acquired infection is also common. Some guidelines recommend them as one of the option for empirical treatment of acute lower UTI. Cephalexin given once daily is an alternative drug for prophylaxis of recurrent cystitis, especially in women likely to get pregnant.

8.Gentamicin (see p. 747) Very effective against most urinary pathogens including Pseudomonas. However, because of narrow margin of safety and need for parenteral administration, it is generally used only on the basis of in vitro bacteriological sensitivity testing. In acute pyelonephritis gentamicin + parenteral amoxicillinclavulanate, may be initiated empirically before bacteriological report becomes available. The newer aminoglycosides may be needed for hospital-acquired infections.

9.Chloramphenicol Though effective in many cases, use

should be restricted (for fear of toxicity) to pyelonephritis

in cases where the causative bacteria is sensitive only to this antibiotic.

10. Tetracyclines They are seldom effective now, because most urinary pathogens have become resistant. Though broad spectrum, they are used only on the basis of sensitivity report and in Ch. trachomatis cystitis.

Urinary pH in relation to use of AMAs

Certain AMAs act better in acidic urine, while others in alkaline urine (see Box). However, specific intervention to produce urine of desired reaction (by administering acidifying or alkalinizing agents) is seldom required (except for methenamine), because most drugs used in UTI attain high concentration in urine and minor changes in urinary pH do not affect clinical outcome. In case of inadequate response or in complicated cases, measurement of urinary pH and appropriate corrective measure may help.

Favourable urinary pH for antimicrobial action

In certain urease positive Proteus (they split urea present in urine into NH3) infections it is impossible to acidify urine. In such cases, acidification should not be attempted and drugs which act better at higher pH should be used.

Urinary infection in patients with renal impairment

This is relatively difficult to treat because most AMAs attain lower urinary concentration. Methenamine mandelate, tetracyclines (except doxycycline) and certain cephalosporins are contraindicated.

Nitrofurantoin, nalidixic acid and aminoglycosides are better avoided. Every effort must be made to cure the infection, because if it persists, kidneys may be further damaged. Bacteriological testing and followup cultures are

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